Strains of mice which quickly resolve infections with a nonlethal isolate of Plasmodium yoelii are exquisitely susceptible to infection with a lethal isolate of this same parasite species. Likewise, strains of mice which live longest following infection with lethal P. yoelii are most susceptible to infection with the nonlethal isolate. The host response phenotype in each case is genetically controlled, and is influenced by H-2 genes as well as genes mapping outside the H-2 complex. Experiments are proposed to study various inbred, H-2 congenic, and recombinant inbred mouse strains to identify, map, and characterize the H-2 and non-H-2 genes which influence the host's ability to resist infection. Parasite-specific humoral and cellular immune responses, as they occur in selected mouse strains, will be characterized throughout the course of infection with different P. yoelii isolates. ELISA, FIPA, and Western blot analyses will be used to characterize the P. yoelii-specific antibody responses. Cell-mediated responses will be analyzed in vivo by DTH, and in vitro by cell proliferation and differential lymphokine production (TI-2, IL-4, IFN gamma and TNF) following stimulation with P. yoelii antigens. T cell Western and Mishell-Dutton cultures will be used to characterize the subsets of cells mediating these responses. finally, we will determine whether or not the parasite-induced antibodies on the surface of uninfected red blood cells are reacting with parasite antigens on the cell surface, or with normal cell surface molecules. The long range goal of this project is to explain how a single set of host genes can regulated responses which mediate increased susceptibility to infection with on isolate of P. yoelii, yet render the host comparatively resistant to infection with a related isolate of the same parasite species.